The δ receptor has been identified as having a role in many bodily functions such as circulatory and pain systems. Ligands for the δ receptor may therefore find potential use as analgesics, and/or as antihypertensive agents. Ligands for the δ receptor have also been shown to possess immunomodulatory activities.
The identification of at least three different populations of opioid receptors (μ, δ and κ) is now well established and all three are apparent in both central and peripheral nervous systems of many species including man. Analgesia has been observed in various animal models when one or more of these receptors has been activated.
With few exceptions, currently available selective opioid δ ligands are peptidic in nature and are unsuitable for administration by systemic routes. One example of a non-peptidic δ-agonist is SNC80 (Bilsky E. J. et al., Journal of Pharmacology and Experimental Therapeutics, 273(1), pp. 359-366 (1995)). There is however still a need for selective δ-agonists having not only improved selectivity, but also an improved side-effect profile.
Thus, the problem underlying the present invention was to find new analgesics having improved analgesic effects, but also with an improved side-effect profile over current μ agonists, as well as having improved systemic efficacy.
Analgesics that have been identified and are existing in the prior art have many disadvantages in that they suffer from poor pharmacokinetics and are not analgesic when administered by systemic routes. Also, it has been documented that preferred δ agonist compounds, described within the prior art, show significant convulsive effects when administered systemically.
We have now found certain compounds that exhibit surprisingly improved properties, i.a. improved δ-agonist potency, in vivo potency, pharmacokinetic, bioavailability, in vitro stability and/or lower toxicity.
Outline of the Invention
The novel compounds according to the present invention are defined by the formula I wherein                R1 is selected from any one of        (i) phenyl;         (ii) pyridinyl         (iii) thienyl         (iv) furanyl         (v) imidazolyl         (vi) triazolyl         (vii) pyrrolyl,         (viii) thiazolyl         (ix) pyridyl-N-oxide where each R1 phenyl ring and R1 heteroaromatic ring may optionally and independently be further substituted by 1, 2 or 3 substituents independently selected from straight and branched C1-C6 alkyl, NO2, CF3, C1-C6 alkoxy, chloro, fluoro, bromo, and iodo. The substitutions on the phenyl ring and on the heteroaromatic ring may take place in any position on said ring systems;        
A further embodiment of the present invention is a compound according to FIG. I wherein R1 is as defined above and each R1 phenyl ring and R1 heteroaromatic ring may independently be further substituted by a methyl group
A further embodiment of the present invention is a compound according to FIG. I wherein R1 is phenyl, pyrrolyl, pyridinyl, thienyl or furanyl, optionally with 1 or 2 of the preferred substituents on the R1 phenyl or R1 heteroaromatic ring.
Another embodiment of the present invention is a compound according to FIG. I wherein R1 is phenyl, pyrrolyl or pyridinyl, optionally with 1 or 2 of the preferred substituents on the R1 phenyl or R1 heteroaromatic ring.
Another embodiment of the present invention is a compound according to FIG. I wherein R1 is thienyl or furanyl, optionally with 1 or 2 of the preferred substituents on the R1 heteroaromatic ring.
Within the scope of the invention are also salts and enantiomers of the compounds of the formula I.
When the R1 phenyl ring and the R1 heteroaromatic ring(s) are substituted, the preferred substituents are independently selected from any one of CF3, methyl, iodo, bromo, fluoro and chloro.
Reaction step A in Scheme 2, vide infra, is performed by reacting an intermediate compound of the general formula II wherein PG is a urethane protecting group such as Boc or CBZ, or a benzyl or a substituted benzyl protecting group, such as 2,4-dimethoxybenzyl, with 8-quinoline boronic acid, using a palladium catalyst, e.g. Pd(PPh3)4, in the presence of a base, e.g. Na2CO3, to give the compounds of general formula III, which is thereafter deprotected, under standard conditions and alkylated using either:                i) a compound of the general formula R1—CH2—X, wherein R1 is as defined above and X is a halogen, preferably bromine or chlorine and a suitable base, or        ii) a compound of the general formula R1—CHO, wherein R1 is as defined above, and a suitable reducing agent,to give compounds of the general formula I.        
Suitable bases to be used in the standard alkylation step i) above include, but are not limited to, triethylamine and potassium carbonate.
Suitable reducing agents to be used in the standard reduction step ii) include, but are not limited to, sodium cyanoborohydride and sodium triacetoxyborohydride.
The novel compounds of the present invention are useful in therapy, especially for the treatment of various pain conditions such as chronic pain, neuropathic pain, acute pain, cancer pain, pain caused by rheumatoid arthritis, migraine, visceral pain etc. This list should however not be interpreted as exhaustive.
Compounds of the invention are useful as immunomodulators, especially for autoimmune diseases, such as arthritis, for skin grafts, organ transplants and similar surgical needs, for collagen diseases, various allergies, for use as anti-tumour agents and anti viral agents.
Compounds of the invention are useful in disease states where degeneration or dysfunction of opioid receptors is present or implicated in that paradigm. This may involve the use of isotopically labelled versions of the compounds of the invention in diagnostic techniques and imaging applications such as positron emission tomography (PET).
Compounds of the invention are useful for the treatment of diarrhoea, depression, anxiety and stress-related disorders such as post-traumatic stress disorders, panic disorder, generalized anxiety disorder, social phobia, and obesessive compulsive disorder; urinary incontinence, various mental illnesses, cough, lung oedema, various gastro-intestinal disorders, e.g. constipation, functional gastrointestinal disorders such as Irritable Bowel Syndrome and Functional Dyspepsia, Parkinson's disease and other motor disorders, traumatic brain injury, stroke, cardioprotection following miocardial infarction, spinal injury and drug addiction, including the treatment of alcohol, nicotine, opioid and other drug abuse and for disorders of the sympathetic nervous system for example hypertension.
Compounds of the invention are useful as an analgesic agent for use during general anaesthesia and monitored anaesthesia care. Combinations of agents with different properties are often used to achieve a balance of effects needed to maintain the anaesthetic state (e.g. amnesia, analgesia, muscle relaxation and sedation). Included in this combination are inhaled anaesthetics, hypnotics, anxiolytics, neuromuscular blockers and opioids.
Also within the scope of the invention is the use of any of the compounds according to the formula I above, for the manufacture of a medicament for the treatment of any of the conditions discussed above.
A further aspect of the invention is a method for the treatment of a subject suffering from any of the conditions discussed above, whereby an effective amount of a compound according to the formula I above, is administered to a patient in need of such treatment.
A further aspect of the present invention is intermediates of the general formula II and III, wherein PG is a urethane protecting group such as Boc or CBZ, or a benzyl or a substituted benzyl protecting group, such as 2,4-dimethoxybenzyl.Methods of Preparation